This project studies the structure-activity relationship (SAR) of the newly discovered antibiotic teixobactin, with the goal of delivering a candidate that has development advantages over the parent compound. Teixobactin is an unusual depsipeptide that is the first member of a novel class of peptidoglycan synthesis inhibitors. Teixobactin targets lipid II, peptidoglycan precursor, and lipid III, teichoic acid precursor. It binds to undecaprenyl-PP-sugars, which are not known to be modified, as opposed to a later lipid II-d-ala-d-ala modifiable form targeted by vancomycin. This unique mode of action, binding to two targets, neither of which is a protein, suggests that resistance will be very difficult to develop. To date, no resistance has been detected. Teixobactin has potent activity against a broad range of Gram-positive bacteria - S. aureus MRSA, S. pneumoniae, B. anthracis, M. tuberculosis, E. faecalis and E. faecium. It is active against resistant forms of these pathogens, including vancomycin-resistant enterococci. Teixobactin was highly efficacious in a murine MRSA septicemia and thigh infection models, and against S. pneumoniae in a lung infection model. Teixobactin itself is moving into development. However, studies of teixobactin have identified a property of the compound that can be improved. Teixobactin has a tendency to gelate in serum, which may present a problem depending on the dosing regimen required for humans (e.g., if higher serum concentrations of the drug are required for humans than mice), and has presented a challenge in administering the compound at higher doses in preclinical studies. Gelation of small peptides is a well-known phenomenon that has been successfully addressed with medicinal chemistry optimization. We will conduct a medicinal chemistry campaign to gain a good understanding of the SAR of the molecule, and use this information to produce analogs that do not gelate but retain potent antibacterial properties. Early, proactive understanding of the SAR of teixobactin would also guide the design of new analogs that could address additional issues that may come up during the development of teixobactin itself. An evaluation of the effect of modifying a variety of positions in the molecule will be conducted, through both semisynthetic and fully synthetic approaches. Several analogs have already been produced by both approaches, which demonstrate the feasibility of the approach. Multiple analogs will be produced and tested for antibacterial activity, lipid II binding, gelation, and in vitro ADMET properties. Three analogs with reduced gelation but favorable in vitro properties will be selected for mouse studies including MTD, PK, and efficacy against MRSA in the thigh infection model. The results of this project will produce a therapeutic lead candidate ready to enter further development including IND-enabling studies.